Poisoning – Hypoglycaemic agent

Disclaimer These guidelines have been produced to guide clinical decision making for the medical, nursing and allied health staff of Perth Children’s Hospital. They are not strict protocols, and they do not replace the judgement of a senior clinician. Clinical common-sense should be applied at all times. These clinical guidelines should never be relied on as a substitute for proper assessment with respect to the particular circumstances of each case and the needs of each patient. Clinicians should also consider the local skill level available and their local area policies before following any guideline.  Read the full CAHS clinical disclaimer

Aim 

To guide PCH Emergency Department (ED) staff with the assessment and management of hypoglycaemic agent poisoning.

This guideline is a general approach to hypoglycaemic agent poisoning. For specific details please contact Poisons Information: 13 11 26 or refer to the Toxicology and Toxinology¹ – Therapeutic Guidelines.

Background¹ 

• Oral hypoglycaemic agents are used for type II diabetes mellitus (non-insulin dependent diabetes).
• Sulfonylurea agents (e.g., glibenclamide – also available as a combination product with metformin, gliclazide – slow release formulations available, glimepiride, glipizide) increase pancreatic insulin secretion and and carry the highest risk of hypoglycaemic toxicity.² 
  • Modified-release preparations may delay onset of symptoms for up to 8-18 hours.
• Metformin is a biguanide agent that acts by decreasing carbohydrate absorption from the gut, increasing glucose uptake in peripheral tissues in the presence of insulin, and reducing hepatic gluconeogenesis.³
  • Should not cause hypoglycaemia when taken as a sole agent.
  • May cause life threatening lactic acidosis, particularly in those with renal or cardiac impairment.
• The thiazolidinedione agents (e.g., pioglitazone) act at a nuclear receptor to improve insulin sensitivity in adipose tissues, skeletal muscles and the liver. Minimal information is available regarding overdose, but no adverse events have been reported.^1,4
  • Should not cause hypoglycaemia when taken as a sole agent.
• DPP-4 inhibitors (e.g., sitagliptin, linagliptin) and GLP-1 receptor agonists (e.g., semaglutide) both act through the glucagon-like peptide-1 pathway. Limited information is available regarding acute overdose, but no adverse events have been reported.^1,4
  • Should not cause hypoglycaemia when taken as a sole agent.
• Sodium-glucose co-transporter-2 (SGLT2) inhibitors (e.g., empagliflozin, dapagliflozin) block reabsorption of glucose in the kidneys. Limited information is available regarding acute overdose, but no adverse events have been reported.^1,4
  • Should not cause hypoglycaemia when taken as a sole agent.
• Combination drugs available as of November 2023 include several DPP-4 inhibitors / metformin combinations, several DPP-4 inhibitor / SGLT2 combinations and several SGLT2 / metformin combinations.⁶ Metformin / glibenclamide combinations are also marketed in Australia.⁴
  • Combination drugs containing sulfonylureas can cause hypoglycaemia.
  • Combination drugs without sulfonylureas should not cause hypoglycaemia.
• Note that insulin can be used in combination with any of these agents and can cause hypoglycaemia.

Resuscitation

Sulfonylurea

• Obtain intravenous (IV) access and administer IV glucose 10% if the patient is hypoglycaemic (Blood Glucose Level (BGL) < 3.3 mmol/L)
  • Age <16 years: 2-5 mL/kg of glucose 10% IV bolus.^7,8
  • Do not start glucose solution prophylactically as it makes risk assessment more difficult. If hypoglycaemia is present or occurs, then start promptly and expedite octreotide infusion.
• Maintain euglycaemia by continued administration of glucose 10% IV infusion at 1-2 mL/kg/hour until octreotide can be started (refer to section below - Antidote).
• BGL needs to be checked at least hourly until the patient is stable and on octreotide.
• Note that recurrent administration of glucose 10% boluses stimulates endogenous insulin release and leads to rebound hypoglycaemia until octreotide is commenced.

Metformin

• Attention to airway, breathing and circulation.
• In the severely intoxicated patient, administration of sodium bicarbonate may be required to acutely manage acidosis and hyperkalaemia until haemodialysis can be performed.

Other Agents

• Resuscitation not required for sole agent ingestion or combination medications containing only other agents (not sulphonylureas or metformin).

Risk Assessment¹

• The sulfonylurea agents may cause prolonged and profound life-threatening hypoglycaemia after accidental paediatric ingestion or deliberate self-poisoning
  • Large overdoses may require treatment for several days.
  • A single tablet in a toddler has the potential to cause life-threatening hypoglycaemia.
  • Peak levels in normal release agents are 4-8 hours.^4,7
  • The onset of hypoglycaemia may be delayed up to 18 hours after ingestion of slow release formulations. Admission for a minimum of 12-24 hours is indicated for blood glucose monitoring.
  • Discharge from hospital should only occur in the daylight hours. 
• Metformin ingestion is not associated with hypoglycaemia in normal patients, but may cause life-threatening lactic acidosis in large overdoses or in the presence of renal or cardiac failure, or when there are co-ingestants which impair renal perfusion.
  • Haemodialysis resolves the acidosis as well as removing metformin from the blood.
  • Nausea and vomiting may occur in smaller overdoses.
  • Asymptomatic patients following accidental exposure to metformin do not require referral to hospital, decontamination or investigation.
  • Children who have taken an unintentional ingestion of up to 1700 mg do not require hospital assessment.
• There are very few reports of accidental ingestion or deliberate self-poisoning of other oral hypoglycaemic agents.
  • There are no reports of hypoglycaemia and it is thought to be unlikely.
  • A conservative approach, with 8 hours of blood sugar monitoring, is reasonable. Other sources suggest that patients with an unintentional overdose can be safely monitored at home.⁹

Typical Clinical Course^1,7,8

Sulfonylureas

Autonomic and central nervous system (CNS) manifestations of hypoglycaemia may include:

• Tachycardia
• Sweating
• Anxiety
• Drowsiness
• Altered mental status
• Coma
• Seizures

Metformin

• Acute metformin overdose is usually asymptomatic.
• Lactic acidosis is usually delayed by several hours and may manifest as:
  • Reduced level of consciousness
  • Nausea, vomiting and diarrhoea
  • Dyspnoea
  • Tachycardia
  • Hypotension
  • Shock, coma and death

Supportive care

• Attention to airway, breathing and circulation are paramount.
• Administration of sodium bicarbonate (as per Emergency Drug Calculator – Kids Health WA) to control severe acidosis in metformin overdose.
  • May need repeated doses at the discretion of senior doctor.

Nursing

• Record a full set of observation on the Observation and Response Chart, with additional information to be recorded on the Clinical Comments chart.
• Record a full set of neurological observations if clinically indicated.
• Commence continuous oximetry and electrocardiogram (ECG) monitoring if indicated.
• Minimum of hourly observations should be recorded whilst in the emergency department.
• Hourly blood glucose levels for the first eight hours or until levels are stable.
• Strict, accurate fluid balance monitoring.

Investigations

Screening tests in deliberate self-poisoning:

• 12-lead ECG and paracetamol levels

Specific investigations as indicated:

• Serial blood glucose levels
• Urea, electrolytes and creatinine (risk of hypokalaemia with insulin stimulation, and dilutional hyponatraemia with glucose solutions)
• Insulin levels may have some role (if available) for sulfonylurea overdoses on the advice of toxicology services.
• Venous or arterial blood gases (including lactate) should be done in metformin overdoses to confirm lactic acidosis and to monitor progress in any unwell patient or following clinical deterioration.

Decontamination

• Activated charcoal (1 g/kg enteral up to 50 g) should be administered to the following patients:⁴
  • The cooperative patient who presents within an hour post-ingestion (or four hours with modified release preparations).
  • The cooperative patient who presents within 2 hours of deliberately self-poisoning with >10 g of metformin.
  • Any intubated patient once the airway is secure.

Enhanced elimination

Sulfonylurea

• Not clinically useful

Metformin

• Haemodialysis rapidly corrects acidosis as well as removing metformin from the body, preventing further lactate production.
• Indications:
  • Any unwell patient with lactic acidosis.
  • Worsening lactic acidosis following acute overdose where signs of clinical instability are present or emerging.
• The requirement for haemodialysis may be prolonged for at least 15 hours.

Antidote^1,5

Sulfonylurea

• Octreotide is a long-acting synthetic analogue of somatostatin and is a specific antidote for the sulfonylurea agents by suppressing insulin release from pancreatic cells.
• Should only be started if hypoglycaemia occurs (i.e., not prophylactically)⁷
• Dose:
  • 4 weeks to 18 years: 1 microgram/kg (maximum 50 micrograms) IV bolus followed by 1 microgram/kg/hour (maximum 25 micrograms/hour).^5,8
• Once the octreotide infusion is running, it is likely that normoglycaemia will be achieved without glucose supplementation. If hypoglycaemia recurs, it should be corrected with IV glucose 10% and the infusion rate of octreotide doubled.^5,8

Octreotide infusion may be ceased when all the following criteria have been met:⁸

• Glucose 10% IV infusion ceased at least 4 hours prior.
• No symptoms of hypoglycaemia
• Bedside BGL > 2.5 mmol/L for more than 4 hours
• Daylight hours - octreotide should not be ceased during evening or night-shift.

Following cessation of octroetide, the BGL should be checked every hour.

The patient can be medically cleared once:

• Normoglycaemia is maintained for 12 hours off octreotide and the patient is on a normal diet
• If available, a plasma insulin level in the normal range at 6 hours after cessation of the octreotide infusion.

Management Summary for Sulfonylurea5,8

If patient has symptoms of hypoglycaemia or BGL < 2.5 mmol/L at any time: Give 2-5 mL/kg of glucose 10% as IV bolus. Check serum insulin level after discussion with toxicology service. Commence glucose 10% IV infusion at 1-2 mL/kg/hour. Give octreotide 1 microgram/kg IV bolus (maximum dose 50 micrograms) Commence octreotide infusion 1 micrograms/kg/hour (maximum 25 micrograms/hour) Dilute 250 micrograms of octreotide in 250 mL glucose 5% = 1 microgram/mL Check bedside BGL hourly. Recheck formal serum BGL and serum insulin level (if available) one hour after commencing octreotide infusion. Admit to hospital High Dependency / Paediatric Critical Care (PCC) Unit. The patient may commence normal diet.

If delayed admission and symptoms of hypoglycaemia occur again, or BGL < 2.5mmol/L, despite octreotide and glucose 10% infusions: Give 5 mL/kg of glucose 10% as IV bolus. Increase glucose 10% IV infusion rate to 2-4 mL/kg/hour. Check bedside BGL hourly. Discuss with PCC for central line placement and commencement of glucose 20% IV infusion. Consider doubling octreotide infusion rate in consultation with PCC and/or toxicology service.

If BgL > 12 mmol/L cease glucose 10% IV infusion

Metformin

• No antidote is available

Disposition

Patients who can usually be managed at home:^1,4,9

• Asymptomatic patients following accidental metformin ingestion.
• Children who acutely ingest less than 1700 mg of metformin.
• Accidental ingestion of agents other than sulphonylurea or metformin containing medications.

Patients who should be evaluated in hospital:

• All patients suspected of deliberate self-poisoning. Also require mental health input.
• All patients potentially exposed to thiazolidinedione or sulfonylurea agents.
• Children who have metformin overdoses of more than 1700mg, or more than 10 g in adult-sized children, mandate observation for at least 8 hours. Patients who remain well with a normal bicarbonate at the end of that period may be medically cleared.

Patients who should be admitted:

• Patients with a BGL < 2.5 mmoL are to be admitted to High Dependency / PCC
• All patients potentially exposed to a sulfonylurea agent should be admitted for observation and monitoring of bedside BGL for a minimum of 18-24 hours.
• Symptomatic patients with hypoglycaemia treated with IV glucose and octreotide.
• Any patients post metformin overdose who presents with or develops lactic acidosis requiring critical care admission, monitoring and assessment for urgent haemodialysis. 

References

1. Toxicology and Toxinology – Therapeutic Guidelines
2. Chu J and Stolbach A. Sulfonylurea Agent Poisoning. UpToDate [Last Updated: 10 January 2023. Cited: 16 January 2024] Available from: Sulfonylurea agent poisoning - UpToDate (health.wa.gov.au)
3. Chu J and Stolbach A. Metformin Poisoning. UpToDate [Last Updated: 12 September 2023. Cited: 16 January 2024] Available from Metformin poisoning - UpToDate
4. MIMS Online January 2024 www.mimsonline.com.au – Cited: 23 November 2023
5. Octreotide. Toxinz Poisons Information online, National Poisons Centre, New Zealand. [Current from: 16 January 2024. Cited: 16 January 2024]  Available from: Octreotide (toxinz.com)
6. NPS MedicineWise External website. Cited: 28 November 2023
7. Life in the Fast Lane. Sulphonylurea toxicity. Sulfonylurea toxicity • LITFL • Toxicology Library Toxicant. Cited 19 February 2024.
8. Clinical Practice Guidelines : Oral Hypoglycaemic Poisoning (rch.org.au) Royal Children’s Hospital Melbourne Cited: 23 November 2023
9. Toxicology of Oral Antidiabetic Medications. Henry A. Spiller; Tama S. Sawyer. Am J Health Syst Pharm. 2006;63(10):929-938

Endorsed by:	Drugs & Therapeutics Committee	Date:	Mar 2024
		Review date:	Jan 2027

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